Pharmaceutical formulations comprising CCR3 antagonists

ABSTRACT

The present invention relates to pharmaceutical compositions containing one or more compounds of formula 1 
                         
wherein
     R 1  is H, C 1-6 -alkyl, C 0-4 -alkyl-C 3-6 -cycloalkyl, C 1-6 -haloalkyl;   R 2  is H, C 1-6 -alkyl;   X is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate;   j is 1 or 2; and
 
processes for the preparation thereof, and their use to treat diseases connected with the CCR3 receptor.

The present invention relates to pharmaceutical compositions containingone or more compounds of formula 1

wherein

-   R¹ is H, C₁₋₆-alkyl, C₀₋₄-alkyl-C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl;-   R² is H, C₁₋₆-alkyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate;-   j is 1 or 2; and    processes for the preparation thereof, and their use to treat    diseases connected with the CCR3 receptor.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338,436-445 (1998); Rollins, Blood, 90, 909-928 (1997); Lloyd, Curr. Opin.Pharmacol., 3, 443-448 (2003); Murray, Current Drug Targets., 7, 579-588(2006); Smit, Eur J Pharmacol., 533,277-88 (2006)).

There are two major classes of chemokines, CXC and CC, depending onwhether the first two cysteines in the amino acid sequence are separatedby a single amino acid (CXC) or are adjacent (CC). The CXC chemokines,such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1a, MIP-1, the monocyte chemotactic proteins (MCP-1,MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, mast cells, dendritic cells, and basophils. Also inexistence are the chemokines lymphotactin-1, lymphotactin-2 (both Cchemokines), and fractalkine (a CXXXC chemokine) that do not fall intoeither of the major chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seventransmembrane-domain proteins (reviewedin Horuk, Trends Pharm. Sci., 15, 159-165 (1994); Murphy, PharmacolRev., 54 (2):227-229 (2002); Allen, Annu. Rev. Immunol., 25, 787-820(2007)) which are termed “chemokine receptors.” On binding their cognateligands, chemokine receptors transduce an intracellular signal throughthe associated trimeric G proteins, resulting in, among other responses,a rapid increase in intracellular calcium concentration, activation ofG-proteins, changes in cell shape, increased expression of cellularadhesion molecules, degranulation, promotion of cell migration, survivaland proliferation. There are at least eleven human chemokine receptorsthat bind or respond to CC chemokines with the following characteristicpatterns: CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1a, MCP-3, MCP-4,RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng.J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B”or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP2, MCP-3, MCP-4, MCP-5] (Charo etal., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng.J. Med., 338, 436-445 (1998)); CCR3 (or “CKR-3” or “CC-CKR-3”)[eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J.Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338,436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”) [TARC, MIP-1a, RANTES,MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or “CKR-5” OR “CCCKR-5”)[MIP-1a, RANTES, MIP-1p] (Sanson, et al., Biochemistry, 35, 3362-3367(1996)); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba et al., J. Biol.Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC](Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8”or “CC-CKR-8”) [1-309, TARC, MIP-1p] (Napolitano et al., J. Immunol.,157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588(1998)); CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3](Bonini etal, DNA and Cell Biol., 16, 1249-1256 (1997)); and CCR31 (or “CKR-11” or“CC-CKR-11”) [MCP-1, MCP-2, MCP-4](Schweickart et al., J Biol Chem, 2759550-9556 (2000)).

In addition to the mammalian chemokine receptors, the Decoy receptorsCCX-CKR, D6 and DARC/Duffy as well proteins expressed by mammaliancytomegaloviruses, herpes viruses and poxviruses, exhibit bindingproperties of chemokine receptors (reviewed by Wells and Schwartz, Curr.Opin. Biotech., 8, 741-748 (1997); Comerford, Bioessays., 29(3):237-47(2007)). Human CC chemokines, such as RANTES and MCP-3, can cause rapidmobilization of calcium via these virally encoded receptors. Receptorexpression may be permissive for infection by allowing for thesubversion of normal immune system surveillance and response toinfection. Additionally, human chemokine receptors, such as CXCR-4,CCR2, CCR3, CCR5 and CCR8, can act as co receptors for the infection ofmammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis, Grave's disease, chronicobstructive pulmonary disease, and atherosclerosis. For example, thechemokine receptor CCR3 is expressed among others on eosinophils,basophils, TH2 cells, alveolar macrophages, mast cells, epithelialcells, microglia cells, astrocytes and fibroblasts. CCR3 plays a pivotalrole in attracting eosinophils to sites of allergic inflammation and insubsequently activating these cells. The chemokine ligands for CCR3induce a rapid increase in intracellular calcium concentration,increased GTP exchange of G-proteins, increased ERK phosphorylation,enhanced receptor internalization, eosinophil shape change, increasedexpression of cellular adhesion molecules, cellular degranulation, andthe promotion of migration. Accordingly, agents that inhibit chemokinereceptors would be useful in such disorders and diseases. In addition,agents that inhibit chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

Therefore, CCR3 is an important target and antagonism of CCR3 is likelyto be effective in the treatment of inflammatory, eosinophilic,immunoregulatory and infectious disorders and diseases (Wegmann, Am JRespir Cell Mol Biol., 36(1):61-67 (2007); Fryer J Clin Invest.,116(1):228-236 (2006); De Lucca, Curr Opin Drug Discov Devel.,9(4):516-524 (2006)).

It has been found and disclosed in WO 2010 115836 that the substitutedpiperidines of formula 1 are highly suitable as CCR3 antagonists, havingless side effects, e.g. inhibition of norepinephrine (NET), dopamine(DAT) or serotonin reuptake transporters (5-HTT) as described by WatsonP S, Bioorg Med Chem Lett., 16(21):5695-5699 (2006), or inhibition of5HT2A, 5HT2C or Dopamine D2 receptors as described by De Lucca, J MedChem., 48(6):2194-2211(2005), or inhibition of the hERG channel asdescribed by De Lucca, Curr Opin Drug Discov Devel., 9(4):516-524(2006), or inhibition of the alpha1B adrenergic receptor.

Thus, these compounds of formula 1 could be used as a medicament inpharmaceutical formulations similar to those known from the prior art(List et al., Arzneiformen-lehre, Wissenschaftliche VerlagsgesellschaftmbH Stuttgart, 4.Auflage, p70ff).

From initial stability experiments with the compounds it became obvious,that the drug substance will require stabilizing effects due to themanufacturing process and/or the formulation ingredients to enablesufficient stability under standard conditions for medicaments accordingto the regulations of Drug Registration Authorities. In addition widelyused standard manufacturing processes like direct compression or aqueousgranulation could not be applied to the compound, due to the physicalcharacteristics of the drug substance such as bulk density or derivingHausner factor, electrostatic charging and surface adhesive properties.These characteristics may significantly influence key features such asflowability and compressibility, which are important for processing ofthe drug substance in order to manufacture a pharmaceutical dosage form.

TABLE 1 Hausner Factor and corresponding Flow Properties Hausner FactorFlow Properties 1.05-1.18 Excellent 1.14-1.19 Good 1.22-1.27 Acceptable1.30-1.54 Bad 1.49-1.61 Very bad >1.67 No flow

The Hausner factor is the ratio of bulk volume to compacted volume,calculated by the formula bulk density/tapped density. Bulk density ismeasured according to Ph. Eur. 2.9.15 (European Pharmacopoeia, 4. Ed.)as poured density. The tapped density is measured according to Ph. Eur.2.9.15 (see also Voigt R., Lehrbuch der pharmazeutischen Technologie[Textbook of Pharmaceutical Technology], Verlag Chemie, 5th Edition,page 148). The Hausner factor is a measure for theflowability/compressibility of powders and ideally should be close to 1.

Thus, the skilled artisan would have expected the need to find a new andinventive pharmaceutical formulation for compounds of formula 1, toprevent the drug substance in the formulation from degradation,especially hydrolytical cleavage which can be caused by air moisture andthe water content of standard pharmaceutical excipients.

DETAILED DESCRIPTION OF THE INVENTION

A first object of the present invention is a pharmaceutical compositioncontaining one or more compounds of formula 1

wherein

-   R¹ is H, C₁₋₆-alkyl, C₀₋₄-alkyl-C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl;-   R² is H, C₁₋₆-alkyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate;-   j is 1 or 2; and    processes for the preparation thereof, and their use to treat    diseases connected with the CCR3 receptor.

Preferred is a pharmaceutical composition containing one or morecompounds of formula 1 wherein

-   R¹ is H, C₁₋₆-alkyl;-   R² is H, C₁₋₆-alkyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate; and-   j is 1 or 2.

Preferred is a pharmaceutical composition containing one or morecompounds of formula 1 wherein

-   R¹ is H, Methyl, Ethyl, Propyl, Butyl;-   R² is H, Methyl, Ethyl, Propyl, Butyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate, preferably chloride; and-   j is 1 or 2, preferably 2.

Preferred is a pharmaceutical composition containing one or morecompounds of formula 1 wherein

-   R¹ is H, Methyl, Ethyl, Propyl, Butyl;-   R² is H, Methyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate, preferably chloride; and-   j is 1 or 2, preferably 2.

Preferred is a pharmaceutical composition containing one or morecompounds of formula 1 wherein

-   R¹ is H, Methyl;-   R² is H, Methyl;-   X is an anion selected from the group consisting of chloride or ½    dibenzoyltartrate, preferably chloride; and-   j is 1 or 2, preferably 2.

Preferred is a pharmaceutical composition containing one or more of theexamples 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 according to the table below asa hydrochloride. Furthermore preferred is a pharmaceutical compositioncontaining one or more of the examples 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10according to the table below as a di-hydrochloride.

Another object of the present invention is the above pharmaceuticaldosage form, wherein it is an orally deliverable dosage form.

Another object of the present invention is the above pharmaceuticaldosage form which is in the form of a tablet (including a film coatedtablet), capsule, pellets, powder or granules.

Another object of the present invention is the above pharmaceuticaldosage form for use as medicament.

Another object of the present invention is the above pharmaceuticaldosage form for the treatment of a disease or condition selected fromrespiratory diseases.

Another object of the present invention is the use of the abovepharmaceutical dosage form for the preparation of a medicament for thetreatment of a disease or condition selected from respiratory diseases.

Another object of the present invention is a process for the treatmentand/or prevention of a disease or condition selected from respiratorydiseases, characterized in that an effective amount of the above definedpharmaceutical dosage form is administered orally to a patient once,twice, thrice or several times daily.

Used Terms and Definitions

The term “about” means 5% more or less of the specified value. Thus,about 100 minutes could also be read as from 95 to 105 minutes.

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the first named subgroup isthe radical attachment point, for example, the substituent“C₁₋₃-alkyl-aryl” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-haloalkyl”, wherein n is an integer from 2 to n,either alone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atomswherein one or more hydrogen atoms are replaced by a halogene atomselected from among fluorine, chlorine or bromine, preferably fluorineand chlorine, particularly preferably fluorine. Examples include: CH₂F,CHF₂, CF₃.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Dosage Forms/Ingredients

Solid pharmaceutical compositions ready for use/ingestion made from acompound of formula 1 comprise powders, granules, pellets, tablets,capsules, chewable tablets, dispersible tables, troches and lozenges. Indetail:

-   -   Capsule formulations according to the invention comprise the        powdery intermediate of a compound of formula 1, an intermediate        blend comprising the powdery intermediate, pellets or granules        obtained by conventional wet-, dry or hot-melt granulation or        hot-melt extrusion or spray-drying of a suitable intermediate        blend, filled in conventional capsules, e.g. hard gelatin or        HPMC capsules.    -   The Capsule formulations from above may also comprise the        powdery intermediate of a compound of formula 1 in a compacted        form.    -   Capsule formulations according to the invention comprise the        compound of formula 1 suspended or diluted in a liquid or        mixture of liquids.    -   Tablet formulations according to the invention comprise such        tablets obtained by direct compression of a suitable final blend        or by tableting of pellets or granules obtained by conventional        wet-, dry or hot-melt granulation or hot-melt extrusion or        spray-drying of a suitable intermediate blend.

Another object of the present invention is a dosage form where apH-adjusting or buffering agent is added for stability improvement ofthe active ingredient. The pH-adjusting/buffering agent may be a basicamino acid, which has an amino group and alkaline characteristics(isoelectric point, p: 7.59-10.76), such as e.g. L-arginine, L-lysine orL-histidine. The pH-adjusting/buffering agent may also be a basic sugaralcohol, like meglumine. A preferred pH-adjusting agent within themeaning of this invention is meglumin or L-arginine. L-arginine andmeglumine have a particular suitable stabilizing effect on thecompositions of this invention, e.g. by suppressing chemical degradationof compounds of formula 1.

Thus, in an embodiment, the present invention is directed to apharmaceutical composition (e.g. an oral solid dosage form, particularlya tablet) comprising a compound of formula 1 and L-arginine or megluminefor stabilizing the composition, particularly against chemicaldegradation; as well as one or more pharmaceutical excipients.

Suitably the pharmaceutical excipients used within this invention areconventional materials such as cellulose and its derivates, D-mannitol,dibasic calcium phosphate, corn starch, pregelatinized starch as afiller, copovidone as a binder, crospovidone as disintegrant, magnesiumstearate as a lubricant, colloidal anhydrous silica as a glidant,hypromellose, polyvinyl alcohol as film-coating agents, polyethyleneglycol as a plasticizer, titanium dioxide, iron oxide red/yellow as apigment, and talc, etc.

In detail pharmaceutical excipients can be a first and second diluent, abinder, a disintegrant and a lubricant; an additional disintegrant andan additional glidant are a further option.

-   -   Diluents suitable for a pharmaceutical composition according to        the invention are cellulose powder, microcrystalline cellulose,        lactose in various crystalline modifications, dibasic        calciumphosphate anhydrous, dibasic calciumphosphate dihydrate,        erythritol, low substituted hydroxypropyl cellulose, mannitol,        starch or modified starch (eg pregelatinized or partially        hydrolysed) or xylitol. Among those diluents dibasic        calciumphosphate anhydrous and microcrystalline cellulose are        preferred.    -   Diluents preferred as the second diluent are the above mentioned        diluents dibasic calciumphosphate anhydrous and microcrystalline        cellulose.    -   Lubricants suitable for a pharmaceutical composition according        to the invention are talc, polyethyleneglycol, calcium behenate,        calcium stearate, sodium stearylfumarate, hydrogenated castor        oil or magnesium stearate. The preferred lubricant is magnesium        stearate.    -   Binders suitable for a pharmaceutical composition according to        the invention are copovidone (copolymerisates of vinylpyrrolidon        with other vinylderivates), hydroxypropyl methylcellulose        (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon        (povidone), pregelatinized starch, stearic-palmitic acid,        low-substituted hydroxypropylcellulose (L-HPC), copovidone and        pregelatinized starch being preferred. The above mentioned        binders pregelatinized starch and L-HPC show additional diluent        and disintegrant properties and can also be used as the second        diluent or the disintegrant.    -   Disintegrants suitable for a pharmaceutical composition        according to the present invention are corn starch,        crospovidone, polacrilin potassium, croscarmellose sodium,        low-substituted hydroxypropylcellulose (L-HPC) or pregelatinized        starch; preferably croscarmellose sodium.    -   As an optional glidant colloidal silicon dioxide can be used.

An exemplary composition according to the present invention comprisesthe diluent dibasic calciumphosphate, microcrystalline cellulose as adiluent with additional disintegrating properties, the bindercopovidone, the disintegrant croscarmellose sodium, and magnesiumstearate as the lubricant.

Typical pharmaceutical compositions comprise (% by weight)

10-50%  active ingredient, 20-88%  diluent 1, 5-50% diluent 2,  1-5%binder, 1-15% disintegrant, and 0.1-5%  lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

10-50%  active ingredient, 20-75%  diluent 1, 5-30% diluent 2, 2-30%binder, 1-12% disintegrant, and 0.1-3%  lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

10-90%  active ingredient, 5-70% diluent 1, 5-30% diluent 2, 0-30%binder, 1-12% disintegrant, and 0.1-3%  lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

10-50%  active ingredient, 20-75%  diluent 1, 5-30% diluent 2, 2-30%binder, 0.5-20%  buffering agent, 1-12% disintegrant, and 0.1-3% lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

30-70%  active ingredient, 20-75%  diluent 1, 5-30% diluent 2, 2-30%binder, 0.5-20%  buffering agent, 1-12% disintegrant, and 0.1-3% lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

30-70%  active ingredient, 10-75%  diluent 1, 5-30% diluent 2, 0-30%binder, 0.5-30%  buffering agent, 1-12% disintegrant, and 0.1-3% lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

30-70% active ingredient, 10-75% diluent 1,  5-30% diluent 2, 0.5-30% buffering agent,  1-12% disintegrant, and  0.1-3% lubricant.

Pharmaceutical compositions containing 10-90% of active ingredient,preferably 30-70% active ingredient (% by weight) are preferred.

A tablet formulation according to the invention may be uncoated orcoated, e.g. film-coated, using suitable coatings known not tonegatively affect the dissolution properties of the final formulation.For instance the tablets can be provided with a seal coat for protectionof the patients environment and clinical staff as well as for moistureprotection purposes by dissolving a high molecular weight polymer aspolyvinylpyrrolidone or polyvinyl alcohol orhydroxypropyl-methylcellulose together with plasticizers, lubricants andoptionally pigments and tensides in water or organic solvent as acetoneand spraying this mixture on the tablet cores inside a coating equipmentas a pan coater or a fluidized bed coater with wurster insert.

Additionally, agents such as beeswax, shellac, cellulose acetatephthalate, polyvinyl acetate phthalate, zein, film forming polymers suchas hydroxypropyl cellulose, ethylcellulose and polymeric methacrylatescan be applied to the tablets, provided that the coating has nosubstantial effect on the disintegration/dissolution of the dosage formand that the coated dosage form is not affected in its stability.

After the dosage form is film-coated, a sugar coating may be appliedonto the sealed pharmaceutical dosage form. The sugar coating maycomprise sucrose, dextrose, sorbitol and the like or mixtures thereof.If desired, colorants or opacifiers may be added to the sugar solution.

Solid formulations of the present invention tend to be hygroscopic. Theymay be packaged using PVC-blisters, PVDC-blisters or a moisture-proofpackaging material such as aluminum foil blister packs, alu/alu blister,transparent or opaque polymer blister with pouch, polypropylene tubes,glass bottles and HDPE bottles optionally containing a child-resistantfeature or may be tamper evident. The primary packaging material maycomprise a desiccant such as molecular sieve or silica gel to improvechemical stability of the active ingredient (API). Opaque packaging suchas colored blister materials, tubes, brown glass bottles or the like canbe used to prolong shelf life of the API by reduction of photodegradation.

Dosages

A dosage range of the compound of formula 1 is usually between 100 and1000 mg, in particular between 200 and 900 mg, 300 and 900 mg or 350 and850 mg or 390 and 810 mg. It is possible to give one or two tablets,preferred are two tablets for a daily oral dosage of 100, 200, 300, 350,400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 mg, preferably350, 400, 450, 750, 800, 850.

The dosages range can be achieved by one tablet or by two tablets;preferably two tablets are administered, each containing half of thedosage.

The application of the active ingredient may occur up to three times aday, preferably one or two times a day. Particular dosage strengths are400 mg or 800 mg.

Methods of Production

Direct Compression

Due to the bad flowability properties of the drug substance and the highHausner factor of approx 1.40 a direct compression process to producetablets is not feasible. Therefore a granulation process (wet or drygranulation) has to be performed.

Wet Granulation

In the wet granulation process the granulation liquid is a solvent suchas water, ethanol, methanol, isopropanol, acetone, preferably ethanol,and contains a binder such as copovidone. The solvent is a volatilecomponent, which does not remain in the final product. The activeingredient and the other excipients with exception of the lubricant arepremixed and granulated with the granulation liquid using a high sheargranulator. The wet granulation step is followed by an optional wetsieving step, drying and dry sieving of the granules. For example afluid bed dryer can then be used for drying.

The dried granules are sieved through an appropriate sieve. Afteraddition of the other excipients with exception of the lubricant themixture is blended in a suitable conventional blender such as a freefall blender followed by addition of the lubricant such as magnesiumstearate and final blending in the blender.

Thus an exemplary wet granulation process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. dissolving a binder such as copovidone in a solvent such as    ethanol at ambient temperature to produce a granulation liquid;-   b. blending a compound of formula 1, a diluent, and a disintegrant    in a suitable mixer, to produce a pre-mix;-   c. moistening the pre-mix with the granulation liquid and    subsequently granulating the moistened pre-mix for example in a high    shear mixer;-   d. optionally sieving the granulated pre-mix through a sieve with a    mesh size of at least 1.0 mm and preferably 3 mm;-   e. drying the granulate at about 40-75° C. and preferably 55-65° C.    inlet air temperature for example in a fluid bed dryer until the    desired loss on drying value in the range of 1-3% is obtained;-   f. delumping the dried granulate for example by sieving through a    sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and-   g. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the excipients such as part of adisintegrant (e.g. corn starch) or a diluent (e.g. pregelatinizedstarch) or an additional disintegrant (crospovidone) can be addedextragranular prior to final blending of step g.

In another alternative version of the process the granulate produced insteps a to e is produced in a one pot high shear granulation process andsubsequent drying in a one pot granulator.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

Fluid Bed Granulation

In the wet granulation process the granulation liquid is a solvent suchas water, ethanol, methanol, isopropanol, acetone, preferably ethanol,and contains a binder such as copovidone. The solvent is a volatilecomponent, which does not remain in the final product. The activeingredient and the other excipients with exception of the lubricant arepremixed and granulated with the granulation liquid using a fluid bedgranulator. The granulation step is followed by a dry sieving of thegranules.

The dried granules are sieved through an appropriate sieve. Afteraddition of the other excipients with exception of the lubricant themixture is blended in a suitable conventional blender such as a freefall blender followed by addition of the lubricant such as magnesiumstearate and final blending in the blender.

Thus an exemplary wet granulation process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. dissolving a binder such as copovidone in a solvent such as    purified water at ambient temperature to produce a granulation    liquid;-   b. blending a compound of formula 1, a diluent, and a disintegrant    in the fluid bed, to produce a pre-mix;-   c. granulate the pre-mix with the granulation liquid in a fluid bed    granulator;-   d. performing the drying step of the granulate at about 40-75° C.    and preferably 55-65° C. inlet air until the desired loss on drying    value in the range of 1-3% is obtained;-   e. delumping the dried granulate for example by sieving through a    sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and-   f. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the excipients such as part of adisintegrant (e.g. corn starch) or a diluent (e.g. pregelatinizedstarch) or an additional disintegrant (crospovidone) can be addedextragranular prior to final blending of step f.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

Hot Melt Granulation

In the hot melt granulation process the binder is a melting agent suchas polyethylene glycol, stearic acid, stearic-palmitic acid, poloxamer,glyceryl monostearate or polyethylene oxide. The active ingredient andthe other excipients with exception of the lubricant are premixed andgranulated with the binder using for example a high shear granulator.The granulation step is followed by a cooling step, and sieving of thegranules.

The granules are sieved through an appropriate sieve. After addition ofthe other excipients with exception of the lubricant the mixture isblended in a suitable conventional blender such as a free fall blenderfollowed by addition of the lubricant such as magnesium stearate andfinal blending in the blender.

Thus an exemplary hot melt granulation process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. blending a compound of formula 1, a diluent, and a disintegrant    in a suitable mixer, to produce a pre-mix;-   b. heating the pre-mix and subsequently granulating the pre-mix for    example in a high shear mixer;-   c. cooling down the granulate at approx 28°;-   d. delumping the granulate for example by sieving through a sieve    with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and-   e. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the excipients such as part of adisintegrant (e.g. corn starch) or a diluent (e.g. pregelatinizedstarch) or an additional disintegrant (crospovidone) can be addedextragranular prior to final blending of step e.

In another alternative version of the process the granulate produced insteps a to c is produced in a one pot high shear granulation.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

Roller Compaction

In the dry granulation process the active ingredient alone or the activeingredient together with the lubricant or the active ingredient and thediluent or a mixture of the diluent and the lubricant are premixed andcompacted using a roller compactor. The dry granulation step is followedby one or two sieving steps.

The granules are sieved through an appropriate sieve. After addition ofthe other excipients with exception of the lubricant the mixture isblended in a suitable conventional blender such as a free fall blenderfollowed by addition of the lubricant such as magnesium stearate andfinal blending in the blender.

Thus an exemplary dry granulation process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. blending a compound of formula 1, a diluent, and a lubricant in a    suitable mixer, to produce a pre-mix;-   b. compacting the pre-mix using a roller compactor;-   c. sieving the granulated pre-mix through a sieve with a mesh size    of at least 0.6 mm and preferably 0.8 mm;-   d. delumping the granulate for example by sieving through a sieve    with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm;-   e adding additional diluent and disintegrant and blend in a suitable    blender; and-   f. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the excipients such as part of adisintegrant or a binder (copovidone) can be added intragranular priorto granulation of step b.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

Hot Melt Extrusion

In the hot melt extrusion process the binder is a melting agent such aspolyethylene glycol, stearic acid, stearic-palmitic acid, poloxamer,vitamin E TGPS, glyceryl monostearate or polyethylene oxide. The activeingredient and the other excipients with exception of the lubricant arepremixed and granulated with the binder using an extruder. Thegranulation step is followed by a cooling step, and sieving of thegranules.

The granules are sieved through an appropriate sieve. After addition ofthe other excipients with exception of the lubricant the mixture isblended in a suitable conventional blender such as a free fall blenderfollowed by addition of the lubricant such as magnesium stearate andfinal blending in the blender.

Thus an exemplary hot melt extrusion process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. blending a compound of formula 1 and a binder in a suitable    mixer, to produce a pre-mix;-   b. granulating the heated pre-mix in an extruder;-   c. optionally sieving the granulated pre-mix through a sieve with a    mesh size of at least 1.0 mm and preferably 3 mm;-   d. delumping the granulate for example by sieving through a sieve    with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm;-   e. and adding a diluent and a disintegrant and blending in a    suitable blender; and-   f. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the excipients such as part of adisintegrant or a diluent or an additional disintegrant can be addedintragranular prior to extrusion of step b.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

EXAMPLES

The present invention is directed to the use of compounds of formula 1for the preparation of pharmaceutical formulations for the treatment ofdiseases connected with the CCR3 receptor. A CCR3 receptor binding testshowing this activity was already disclosed in WO 2010 115836. Ki valuesfor the compounds of formula 1 (human Eotaxin-1 at human CCR3-Receptor)are shown in the table below. As used herein, “activity” is intended tomean a compound demonstrating an inhibition of 50% at μM or higher ininhibition when measured in the aforementioned assays. Such a result isindicative of the intrinsic activity of the compounds as inhibitor ofCCR3 receptor activity.

The examples of compounds of formula 1 can be synthesized according tothe description of WO 2010 115836, which is herewith incorporated byreference. The salts of these examples can be formed by crystallizingthe free bases from a solution containing HCl. Preferably the examples1, 2 3, 4, 5, 6, 7, 8, 9 and 10 are in form of the dihydrochloride.

hCCR3 # Structure Ki (nM)  1.

10.4  2.

 3.2  3.

 3.5  4.

 4.3  5.

 4.6  6.

 4.0  7.

 5.2  8.

 2.3  9.

 4.2 10.

 1.7

Example for Degradation

High Performance Liquid Chromatography (HPLC) with a reversed phasecolumn and a gradient with buffer/acetonitrile and UV quantificationwere used for the quantification of degradation products

The stability results of storage under stress conditions (bottles at 40°C./60° C.) and open storage at 25° C./60% r.h. for pure drug substanceand different tablet formulation provide evidence that due to theformulation significant stability improvement was achieved.

The drug substance stored open for one week at 25° C./60% r.h.liquefies, which is accompanied by degradation (total degradation of2.5%). Stored in a close container for 3 months a total degradation of43% was quantified.

The different formulation principles developed show under the sameconditions and similar packaging no degradation (alu/alu blister nodegradation product >0.1% after 3 month) and under open storageconditions at 25° C./60% r.h. (1 week) a total degradation of 0.7%.

According to internationally accepted guidelines (e.g. ICH Q3b) theimproved stability characteristics enable the administration of the newchemical entity to patients.

Tablets

With the compounds above i.e. examples 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10in form of the hydrochloride or examples 1, 2 3, 4, 5, 6, 7, 8, 9 and 10in form of the dihydrochloride the following non-limiting examples forsolid pharmaceutical compositions can be made:

Example 1—Tablet Formulation—Wet Granulation

Copovidone is dissolved in ethanol at ambient temperature to produce agranulation liquid. An active CCR3 antagonist ingredient (one or morecompound of formula 1), lactose and part of the crospovidone are blendedin a suitable mixer, to produce a pre-mix. The pre-mix is moistened withthe granulation liquid and subsequently granulated. The moist granulateis optionally sieved through a sieve with a mesh size of 1.6-3.0 mm. Thegranulate is dried at 45° C. in a suitable dryer to a residual moisturecontent corresponding to 1-3% loss on drying. The dried granulate issieved through a sieve with a mesh size of 1.0 mm. The granulate isblended with part of the crospovidone and microcrystalline cellulose ina suitable mixer. Magnesium stearate is added to this blend afterpassing through a 1.0 mm sieve for delumping. Subsequently the finalblend is produced by final blending in a suitable mixer and compressedinto tablets. The following tablet composition can be obtained:

Component mg/tablet %/tablet Active ingredient 28.500 30.0 Crospovidone1.500 1.6 Lactose 28.000 29.5 Copovidone 3.000 3.2 −>Total (granulate)61.000 −>64.3 Microcrystalline cellulose 31.000 32.6 Crospovidone 2.5002.6 Magnesium stearate 0.500 0.5 Total 95.000 100.000

Example 2—Tablet Formulation—Melt Granulation

An active CCR3 antagonist ingredient (one or more compound of formula1), lactose, part of the mcc (microcrystalline cellulose), polyethyleneglycole, lactose and part of the crospovidone are blended in a suitablemixer, to produce a pre-mix. The pre-mix is heated in a high shear mixerand subsequently granulated. The hot granulate is cooled down to roomtemperature and sieved through a sieve with a mesh size of 1.0 mm. Thegranulate is blended with part of the crospovidone and microcrystallinecellulose in a suitable mixer. Magnesium stearate is added to this blendafter passing through a 1.0 mm sieve for delumping. Subsequently thefinal blend is produced by final blending in a suitable mixer andcompressed into tablets. The following tablet composition can beobtained:

Component mg/tablet %/tablet Active ingredient 28.500 30.0 Crospovidone1.500 1.6 Lactose 11.000 11.6 Polyethylene glycole 14.300 15.1 MCC 5.7006.0 −>Total (granulate) 61.000 −>64.3 Microcrystalline cellulose 31.00032.6 Crospovidone 2.500 2.6 Magnesium stearate 0.500 0.5 Total 95.000100.000

Example 3—Tablet Formulation—Hot Melt Granulation

An active CCR3 antagonist ingredient (one or more compound of formula1), mannit, polyethylene glycole and part of the crospovidone areblended in a suitable mixer, to produce a pre-mix. The pre-mix is heatedin a high shear mixer and subsequently granulated. The hot granulate iscooled down to room temperature and sieved through a sieve with a meshsize of 1.0 mm. The granulate is blended with part of the crospovidoneand mannit in a suitable mixer. Magnesium stearate is added to thisblend after passing through a 1.0 mm sieve for delumping. Subsequentlythe final blend is produced by final blending in a suitable mixer andcompressed into tablets. The following tablet composition can beobtained:

Component mg/tablet %/tablet Active ingredient 28.500 30.0 Crospovidone1.500 1.6 Mannit 16.700 17.6 Polyethylene glycole 14.300 15.1 −>Total(granulate) 61.000 −>64.3 Mannit 31.000 32.6 Crospovidone 2.500 2.6Magnesium stearate 0.500 0.5 Total 95.000 100.000

Example 4—Tablet Formulation—Hot Melt Extrusion

An active CCR3 antagonist ingredient (one or more compound of formula 1)and stearic-palmitic acid are blended in a suitable mixer, to produce apre-mix. The pre-mix is extruded in a twin-screw-extruder andsubsequently granulated. The granulate is sieved through a sieve with amesh size of 1.0 mm. The granulate is blended with mannit andcrospovidone in a suitable mixer. Magnesium stearate is added to thisblend after passing through a 1.0 mm sieve for delumping. Subsequentlythe final blend is produced by final blending in a suitable mixer andcompressed into tablets. The following tablet composition can beobtained:

Component mg/tablet %/tablet Active ingredient 28.500 30.0Stearic-palmitic acid 27.500 28.9 −>Total (granulate) 56.000 −>58.9Mannit 32.600 34.3 Crospovidone 5.600 5.9 Magnesium stearate 0.800 0.9Total 95.000 100.000

Example 5—Tablet Formulation—Hot Melt Extrusion

An active CCR3 antagonist ingredient (one or more compound of formula 1)and stearic-palmitic acid are blended in a suitable mixer, to produce apre-mix. The pre-mix is extruded in a twin-screw-extruder andsubsequently granulated. The granulate is sieved through a sieve with amesh size of 1.0 mm. The granulate is directly filled into hardcapsules. The following capsule composition can be obtained:

Component mg/tablet %/tablet Active ingredient 70.000 70.0Stearic-palmitic acid 30.000 30.0 −>Total (granulate) 100.000 −>100.0Capsule 90.000 — Total 190.000 100.000

Example 6—Tablet Formulation—Roller Compaction

An active CCR3 antagonist ingredient (one or more compound of formula1), part of mannit and crospovidone and magnesium stearate are blendedin a suitable mixer, to produce a pre-mix. The pre-mix is compacted witha roller compactor and subsequently granulated. Optionally, thegranulate is sieved through a sieve with a mesh size of 0.8 mm. Thegranulate is blended with part of mannit and crospovidone in a suitablemixer. Magnesium stearate is added to this blend after passing through a1.0 mm sieve for delumping. Subsequently the final blend is produced byfinal blending in a suitable mixer and compressed into tablets. Thefollowing tablet composition can be obtained:

Component mg/tablet %/tablet Active ingredient 28.500 30.0 Crospovidone1.400 1.5 Mannit 34.600 36.4 Magnesium stearate 0.500 0.5 −>Total(granulate) 65.000 −>68.4 Mannit 27.000 28.4 Copovidone 1.600 1.7Crospovidone 0.950 1.0 Magnesium stearate 0.450 0.5 Total 95.000 100.000

Example 7.1—Tablet Formulation—Roller Compaction

An active CCR3 antagonist ingredient (one or more compound of formula 1)and magnesium stearate are blended in a suitable mixer, to produce apre-mix. The pre-mix is compacted with a roller compactor andsubsequently granulated. Optionally, the granulate is sieved through asieve with a mesh size of 0.8 mm. The granulate is blended with mannitand croscarmellose sodium in a suitable mixer. Magnesium stearate isadded to this blend after passing through a 1.0 mm sieve for delumping.Subsequently the final blend is produced by final blending in a suitablemixer and compressed into tablets. The following tablet composition canbe obtained:

Component mg/tablet %/tablet Active ingredient 114.200 66.0 Magnesiumstearate 1.800 1.0 −>Total (granulate) 116.000 −>67.0 Mannit 51.000 29.5Croscarmellose sodium 3.500 2.0 Magnesium stearate 2.500 1.5 Total173.000 100.000

Example 7.2—Tablet Formulation—Roller Compaction

An active CCR3 antagonist ingredient (one or more compound of formula 1)is compacted with a roller compactor and subsequently granulated.Optionally, the granulate is sieved through a sieve with a mesh size of0.8 mm. The granulate is blended with dibasic calciumphosphateanhydrous, microcrystalline cellulose and croscarmellose sodium in asuitable mixer. Magnesium stearate is added to this blend after passingthrough a 1.0 mm sieve for delumping. Subsequently the final blend isproduced by final blending in a suitable mixer and compressed intotablets. The following tablet composition can be obtained:

Component mg/tablet %/tablet Active ingredient 114.000 66.0Microcrystalline cellulose 17.400 10.0 Dibasic calciumphosphate 32.10018.5 Croscarmellose sodium 6.900 4.0 Magnesium stearate 2.600 1.5 Total173.000 100.000

Example 8—Tablet Formulation—Roller Compaction

An active CCR3 antagonist ingredient (one or more compound of formula 1)and magnesium stearate are blended in a suitable mixer, to produce apre-mix. The pre-mix is compacted with a roller compactor andsubsequently granulated. Optionally, the granulate is sieved through asieve with a mesh size of 0.8 mm. The granulate is blended withmicrocrystalline cellulose and crospovidone in a suitable mixer.Magnesium stearate is added to this blend after passing through a 1.0 mmsieve for delumping. Subsequently the final blend is produced by finalblending in a suitable mixer and compressed into tablets. The followingtablet composition can be obtained:

Component mg/tablet %/tablet Active ingredient 114.200 66.0 Magnesiumstearate 1.800 1.0 −>Total (granulate) 116.000 −>67.0 MCC 51.000 29.5Crospovidone 3.500 2.0 Magnesium stearate 2.500 1.5 Total 173.000100.000

Example 9.1—Coated Tablet Formulation

Tablet cores according above mentioned formulations can be used toproduce film-coated tablets. Hydroxypropyl methylcellulose (HPMC),polyethylene glycol, talc, titanium dioxide and iron oxide are suspendedin purified water in a suitable mixer at ambient temperature to producea coating suspension. The tablet cores are coated with the coatingsuspension to a weight gain of about 3% to produce film-coated tablets.The following film coating composition can be obtained:

Component mg/tablet %/tablet Hypromellose (HPMC) 2.40 48.0 Polyethyleneglycol 6000 0.70 14.0 Titanium dioxide 0.90 18.0 Talcum 0.90 18.0 Ironoxide red 0.10 2.0 Purified water (volatile component) — — Total 5.00100.0

Example 9.2—Coated Tablet Formulation

Tablet cores according above mentioned formulations can be used toproduce film-coated tablets. Polyvinyl alcohol (PVA), polyethyleneglycol, talc, titanium dioxide and iron oxide are suspended in purifiedwater in a suitable mixer at ambient temperature to produce a coatingsuspension. The tablet cores are coated with the coating suspension to aweight gain of about 3% to produce film-coated tablets. The followingfilm coating composition can be obtained:

Component mg/tablet %/tablet Polyvinyl alcohol (PVA) 2.00 40.0Polyethylene glycol 6000 1.0 20.2 Titanium dioxide 1.11 22.1 Talcum 0.7414.8 Iron oxide red 0.08 1.6 Iron oxide yellow 0.07 1.4 Purified water(volatile component) — — Total 5.00 100.0Indications

The compounds of formula 1 as described above are useful formanufacturing a pharmaceutical formulation for the prevention and/ortreatment of diseases wherein the activity of a CCR3-receptor isinvolved.

Preferred is the manufacturing of a medicament for the prevention and/ortreatment of a wide variety of inflammatory, infectious, andimmunoregulatory disorders and diseases of the respiratory orgastrointestinal complaints, inflammatory diseases of the joints andallergic diseases of the nasopharynx, eyes, and skin, including asthmaand allergic diseases, eosinophilic diseases, infection by pathogenicmicrobes (which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis, aswell as diseases associated with abnormal enhanced neovascularizationsuch as age-related macular degeneration (AMD), including dryage-related macular degeneration (dAMD) and wet age-related maculardegeneration (wAMD); diabetic retinopathy and diabetic macular edema,retinopathy of prematurity (ROP), central retinal vein occlusion (CRVO),nasal polyposis, eosinophilic esophagitis, eosinophillic gastroenteritis(e.g. eosinophilic gastritis and eosinophilic ententeritis),hypereosinophilic syndrome and Churg Strauss syndrome.

Age-related macular degeneration is a leading cause of blindnessworldwide. Most blindness in AMD results from invasion of the retina bychoroidal neovascularization. CCR3 is specifically expressed inchoroidal neovascular endothelial cells of AMD patients. In an oftenused mouse animal model for AMD laser injury-induced choroidalneovascularization was diminished by genetic depletion of CCR3 or CCR3ligands as well as by treatment of the mice with an anti-CCR3 antibodyor an CCR3 antagonist (Takeda et al, Nature 2009, 460(7252):225-30).

Most preferred is the manufacturing of a medicament for the preventionand/or treatment of e.g. inflammatory or allergic diseases andconditions, including respiratory allergic diseases such as asthma,perennial and seasonal allergic rhinitis, allergic conjunctivitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulites (e. g., Well's syndrome), eosinophilicpneumonias (e. g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e. g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e. g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);non-allergic asthma; Exercise induced bronchoconstriction; systemicanaphylaxis or hypersensitivity responses, drug allergies (e. g., topenicillin, cephalosporins), eosinophilia-myalgia syndrome due to theingestion of contaminated tryptophan, insect sting allergies; autoimmunediseases, such as rheumatoid arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, myasthenia gravis, immunethrombocytopenia (adult ITP, neonatal thrombocytopenia, paediatric ITP),immune haemolytic anaemia (auto-immune and drug induced), Evans syndrome(platelet and red cell immune cytopaenias), Rh disease of the newborn,Goodpasture's syndrome (anti-GBM disease), Celiac, Auto-immunecardio-myopathy juvenile onset diabetes; glomerulonephritis, autoimmunethyroiditis, Behcet's disease; graft rejection (e. g., intransplantation), including allograft rejection or graftversus-hostdisease; inflammatory bowel diseases, such as Crohn's disease andulcerative colitis; spondyloarthropathies; scleroderma; psoriasis(including Tcell mediated psoriasis) and inflammatory dermatoses such asan dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria; vasculitis (e. g., necrotizing, cutaneous, andhypersensitivity vasculitis); erythema nodosum; eosinophilic myositis,eosinophilic fasciitis; cancers with leukocyte infiltration of the skinor organs; chronic obstructive pulmonary disease, age-related maculardegeneration (AMD), diabetic retinopathy and diabetic macular edema.

In another aspect of the invention preferred is the manufacturing of amedicament for the prevention and/or treatment of diseases selected fromage-related macular degeneration (AMD), including dry age-relatedmacular degeneration (dAMD) and wet age-related macular degeneration(wAMD); diabetic retinopathy and diabetic macular edema; and retinopathyof prematurity (ROP).

The invention claimed is:
 1. A method comprising administering apharmaceutical composition comprising as an active ingredient one ormore compounds of formula 1

wherein R¹ is H, C₁₋₆-alkyl, C₀₋₄-alkyl-C₃₋₆-cycloalkyl, orC₁₋₆-haloalkyl; R² is H or C₁₋₆-alkyl; X is chloride; and j is 2, afirst diluent that is dibasic calcium phosphate anhydrous, a seconddiluent, a binder, a disintegrant and a lubricant.
 2. The methodaccording to claim 1, wherein R¹ is H or Methyl; and R² is H or Methyl.3. The method according to claim 1, wherein the composition comprises anadditional disintegrant.
 4. The method according to claim 3, wherein theadditional disintegrant is crospovidone.
 5. The method according toclaim 1, wherein the composition comprises a glidant.
 6. The methodaccording to claim 1, wherein the second diluent is cellulose powder,dibasic calcium phosphate dihydrate, erythritol, low substitutedhydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol. 7.The method according to claim 1, wherein the lubricant is talc,polyethyleneglycol, calcium behenate, calcium stearate, hydrogenatedcastor oil or magnesium stearate.
 8. The method according to claim 1,wherein the binder is copovidone, hydroxypropyl methylcellulose,hydroxypropylcellulose, or polyvinylpyrrolidone.
 9. The method accordingto claim 1, wherein the disintegrant is croscarmellose sodium.
 10. Themethod according to claim 5, wherein the glidant is colloidal silicondioxide.
 11. The method according to claim 1, wherein the compositioncomprises 10-90% active ingredient,  5-70% dibasic calcium phosphateanhydrous,  5-30% second diluent,  0-30% binder,  1-12% disintegrant,and 0.1-3%   lubricant.


12. The method according to claim 1, wherein the composition comprises30-70% active ingredient, 10-75% dibasic calcium phosphate anhydrous, 5-30% second diluent,  0-30% binder, 0.5-20%  buffering agent,  1-12%disintegrant, and 0.1-3%   lubricant.


13. The method according to claim 1, wherein the composition is in thedosage form of a capsule, a tablet or a film-coated tablet.
 14. Themethod of claim 13, wherein the dosage form comprises a 2-4% film coat.15. The method of claim 14, wherein the film coat comprises afilm-forming agent, a plasticizer, a glidant and optionally one or morepigments.
 16. The method of claim 15, wherein the film coat comprisesPolyvinyl alcohol (PVA) or hydroxypropylmethylcellulose (HPMC),polyethylene glycol (PEG), talc, titanium dioxide and iron oxide.